Do you know when the inhaler is empty?

BACKGROUND: Medication review is recommended at asthma appointments. The presence of propellant in the metered dose inhalers (MDIs) makes it challenging to identify when the inhaler is empty. The COVID-19 pandemic has resulted in move towards more virtual monitoring of care. We aimed to evaluate if patients identify when the inhaler is empty and the method of inhaler disposal. METHODS: Prospective, multicentre quality improvement project. Data collected from children with asthma and other respiratory conditions. OUTCOME MEASURES: Children/carers attending hospital were asked how they identify an empty salbutamol inhaler; dose counters in the preventer inhalers and disposal practices were reviewed. RESULTS: 157 patients recruited. 125 (73.5%) patients deemed an empty inhaler as either full/partially full. 12 of 66 (18.2%) preventer inhalers with a dose counter were empty. 83% disposed their inhalers in a dustbin. CONCLUSIONS: Patients cannot reliably identify when their MDI is empty. There is an urgent need for improving inhaler technology and providing appropriate guidance on how to identify when an MDI is empty.

Endocrine immune-related adverse events: Adrenal, parathyroid, diabetes insipidus, and lipoatrophy.

Immune checkpoint inhibitors are being prescribed increasingly widely for a range of malignancies. They are effective at treating certain cancers, but also have significant side effects. Evidence suggests that efficacy is greatest in patients who experience one or more immune-related adverse events (irAEs). Common irAEs include skin and hepatic reactions, and a range of immune-related endocrinopathies. These include hypophysitis, thyroid disease, and autoimmune diabetes mellitus, and rarer endocrinopathies such as primary adrenal insufficiency, diabetes insipidus, parathyroid disease, autoimmune polyglandular syndrome, lipodystrophy, and ACTH-dependent Cushing's syndrome. Herein, we review the current literature related to these rarer immunotherapy-induced endocrinopathies.

Verification and Validation of Digital Pathology (Whole Slide Imaging) for Primary Histopathological Diagnosis: All Wales Experience.

AIMS: The study is aimed to verify Aperio AT2 scanner for reporting on the digital pathology platform (DP) and to validate the cohort of pathologists in the interpretation of DP for routine diagnostic histopathological services in Wales, United Kingdom. MATERIALS METHODS AND RESULTS: This was a large multicenter study involving seven hospitals across Wales and unique with 22 (largest number) pathologists participating. 7491 slides from 3001 cases were scanned on Leica Aperio AT2 scanner and reported on digital workstations with Leica software of e-slide manager. A senior pathology fellow compared DP reports with authorized reports on glass slide (GS). A panel of expert pathologists reviewed the discrepant cases under multiheader microscope to establish ground truth. 2745 out of 3001 (91%) cases showed complete concordance between DP and GS reports. Two hundred and fifty-six cases showed discrepancies in diagnosis, of which 170 (5.6%) were deemed of no clinical significance by the review panel. There were 86 (2.9%) clinically significant discrepancies in the diagnosis between DP and GS. The concordance was raised to 97.1% after discounting clinically insignificant discrepancies. Ground truth lay with DP in 28 out of 86 clinically significant discrepancies and with GS in 58 cases. Sensitivity of DP was 98.07% (confidence interval [CI] 97.57-98.56%); for GS was 99.07% (CI 98.72-99.41%). CONCLUSIONS: We concluded that Leica Aperio AT2 scanner produces adequate quality of images for routine histopathologic diagnosis. Pathologists were able to diagnose in DP with good concordance as with GS. STRENGTHS AND LIMITATIONS OF THIS STUDY: Strengths of this study - This was a prospective blind study. Different pathologists reported digital and glass arms at different times giving an ambience of real-time reporting. There was standardized use of software and hardware across Wales. A strong managerial support from efficiency through the technology group was a key factor for the implementation of the study. LIMITATIONS: This study did not include Cytopathology and in situ hybridization slides. Difficulty in achieving surgical pathology practise standardization across the whole country contributed to intra-observer variations.

Systematic Matter and Binding-Energy Distributions from a Dispersive Optical Model Analysis.

We present the first systematic nonlocal dispersive optical model analysis using both bound-state and scattering data of ^{16,18}O, ^{40,48}Ca, ^{58,64}Ni, ^{112,124}Sn, and ^{208}Pb. In all systems, roughly half the total nuclear binding energy is associated with the most-bound 10% of the total nucleon density. The extracted neutron skins reveal the interplay of asymmetry, Coulomb, and shell effects on the skin thickness. Our results indicate that simultaneous optical model fits of inelastic scattering and structural data on isotopic pairs are effective for constraining asymmetry-dependent nuclear structural quantities otherwise difficult to observe experimentally.

Histological validation of a type 1 diabetes clinical diagnostic model for classification of diabetes.

AIMS: Misclassification of diabetes is common due to an overlap in the clinical features of type 1 and type 2 diabetes. Combined diagnostic models incorporating clinical and biomarker information have recently been developed that can aid classification, but they have not been validated using pancreatic pathology. We evaluated a clinical diagnostic model against histologically defined type 1 diabetes. METHODS: We classified cases from the Network for Pancreatic Organ donors with Diabetes (nPOD) biobank as type 1 (n = 111) or non-type 1 (n = 42) diabetes using histopathology. Type 1 diabetes was defined by lobular loss of insulin-containing islets along with multiple insulin-deficient islets. We assessed the discriminative performance of previously described type 1 diabetes diagnostic models, based on clinical features (age at diagnosis, BMI) and biomarker data [autoantibodies, type 1 diabetes genetic risk score (T1D-GRS)], and singular features for identifying type 1 diabetes by the area under the curve of the receiver operator characteristic (AUC-ROC). RESULTS: Diagnostic models validated well against histologically defined type 1 diabetes. The model combining clinical features, islet autoantibodies and T1D-GRS was strongly discriminative of type 1 diabetes, and performed better than clinical features alone (AUC-ROC 0.97 vs. 0.95; P = 0.03). Histological classification of type 1 diabetes was concordant with serum C-peptide [median < 17 pmol/l (limit of detection) vs. 1037 pmol/l in non-type 1 diabetes; P < 0.0001]. CONCLUSIONS: Our study provides robust histological evidence that a clinical diagnostic model, combining clinical features and biomarkers, could improve diabetes classification. Our study also provides reassurance that a C-peptide-based definition of type 1 diabetes is an appropriate surrogate outcome that can be used in large clinical studies where histological definition is impossible. Parts of this study were presented in abstract form at the Network for Pancreatic Organ Donors Conference, Florida, USA, 19-22 February 2019 and Diabetes UK Professional Conference, Liverpool, UK, 6-8 March 2019.

Untargeted metabolomic analysis in non-fasted diabetic dogs by UHPLC-HRMS.

INTRODUCTION: We recently identified variances in serum metabolomic profiles between fasted diabetic and healthy dogs, some having similarities to those identified in human type 1 diabetes. OBJECTIVES: Compare untargeted metabolomic profiles in the non-fasted state. METHODS: Serum from non-fasted diabetic (n = 6) and healthy control (n = 6) dogs were analyzed by liquid chromatography-high resolution mass spectrometry. RESULTS: Clear clustering of metabolites between groups were observed, with multiple perturbations identified that were similar to those previously observed in fasted diabetic dogs. CONCLUSION: These findings further support the development of targeted assays capable of detecting metabolites that may be useful as biomarkers of canine diabetes.

Impact of Inter-Individual Variance in the Expression of a Radiation-Responsive Gene Panel Used for Triage.

In previous studies we determined a gene expression signature in baboons for predicting the severity of hematological acute radiation syndrome. We subsequently validated a set of eight of these genes in leukemia patients undergoing total-body irradiation. In the current study, we addressed the effect of intra-individual variability on the basal level of expression of those eight radiation-responsive genes identified previously, by examining baseline levels in 200 unexposed healthy human donors (122 males and 88 females with an average age of 46 years) using real-time PCR. In addition to the eight candidate genes ( DAGLA, WNT3, CD177, PLA2G16, WLS, POU2AF1, STAT4 and PRF1), we examined two more genes ( FDXR and DDB2) widely used in ex vivo whole blood experiments. Although significant sex- (seven genes) and age-dependent (two genes) differences in expression were found, the fold changes ranged only between 1.1-1.6. These were well within the twofold differences in gene expression generally considered to represent control values. Age and sex contributed less than 20-30% to the complete inter-individual variance, which is calculated as the fold change between the lowest (reference) and the highest Ct value minimum-maximum fold change (min-max FC). Min-max FCs ranging between 10-17 were observed for most genes; however, for three genes, min-max FCs of complete inter-individual variance were found to be 37.1 ( WNT3), 51.4 ( WLS) and 1,627.8 ( CD177). In addition, to determine whether discrimination between healthy and diseased baboons might be altered by replacing the published gene expression data of the 18 healthy baboons with that of the 200 healthy humans, we employed logistic regression analysis and calculated the area under the receiver operating characteristic (ROC) curve. The additional inter-individual variance of the human data set had either no impact or marginal impact on the ROC area, since up to 32-fold change gene expression differences between healthy and diseased baboons were observed.

Neutron Skin Thickness of

A nonlocal dispersive optical-model analysis has been carried out for neutrons and protons in ^{48}Ca. Elastic-scattering angular distributions, total and reaction cross sections, single-particle energies, the neutron and proton numbers, and the charge distribution have been fitted to extract the neutron and proton self-energies both above and below the Fermi energy. From the single-particle propagator resulting from these self-energies, we have determined the charge and neutron matter distributions in ^{48}Ca. A best fit neutron skin of 0.249±0.023 fm is deduced, but values up to 0.33 fm are still consistent. The energy dependence of the total neutron cross sections is shown to have a strong sensitivity to the skin thickness.

The Rb1 tumour suppressor gene modifies telomeric chromatin architecture by regulating TERRA expression.

The tumour suppressor gene (Rb1) is necessary for the maintenance of telomere integrity in osteoblastic cells. We now show that the compaction of telomeric chromatin and the appropriate histone modifications of telomeric DNA are both dependent upon Rb1-mediated transcription of the telomere-derived long non-coding RNA TERRA. Expression of TERRA was reduced in Rb1 haploinsufficient cells, and further decreased by shRNA-mediated reduction of residual Rb1 expression. Restoration of Rb1 levels through lentiviral transduction was sufficient to reestablish both transcription of TERRA and condensation of telomeric chromatin. The human chromosome 15q TERRA promoter contains predicted retinoblastoma control elements, and was able to confer Rb1-dependent transcription upon a promoterless reporter gene. Chromatin immunoprecipitation revealed preferential binding of phosphorylated over non-phosphorylated Rb1 at the TERRA promoter. As Rb1-deficient cells show increased genomic instability we suggest that this novel non-canonical action of Rb1 may contribute to the tumour suppressive actions of Rb1.

The effects of policy actions to improve population dietary patterns and prevent diet-related non-communicable diseases: scoping review.

Poor diet generates a bigger non-communicable disease (NCD) burden than tobacco, alcohol and physical inactivity combined. We reviewed the potential effectiveness of policy actions to improve healthy food consumption and thus prevent NCDs. This scoping review focused on systematic and non-systematic reviews and categorised data using a seven-part framework: price, promotion, provision, composition, labelling, supply chain, trade/investment and multi-component interventions. We screened 1805 candidate publications and included 58 systematic and non-systematic reviews. Multi-component and price interventions appeared consistently powerful in improving healthy eating. Reformulation to reduce industrial trans fat intake also seemed very effective. Evidence on food supply chain, trade and investment studies was limited and merits further research. Food labelling and restrictions on provision or marketing of unhealthy foods were generally less effective with uncertain sustainability. Increasingly strong evidence is highlighting potentially powerful policies to improve diet and thus prevent NCDs, notably multi-component interventions, taxes, subsidies, elimination and perhaps trade agreements. The implications for policy makers are becoming clearer.

Validation of a rapid type 1 diabetes autoantibody screening assay for community-based screening of organ donors to identify subjects at increased risk for the disease.

The Network for Pancreatic Organ donors with Diabetes (nPOD) programme was developed in response to an unmet research need for human pancreatic tissue obtained from individuals with type 1 diabetes mellitus and people at increased risk [i.e. autoantibody (AAb)-positive] for the disease. This necessitated the establishment of a type 1 diabetes-specific AAb screening platform for organ procurement organizations (OPOs). Assay protocols for commercially available enzyme-linked immunosorbent assays (elisas) determining AAb against glutamic acid decarboxylase (GADA), insulinoma-associated protein-2 (IA-2A) and zinc transporter-8 (ZnT8A) were modified to identify AAb-positive donors within strict time requirements associated with organ donation programmes. These rapid elisas were evaluated by the international islet AAb standardization programme (IASP) and used by OPO laboratories as an adjunct to routine serological tests evaluating donors for organ transplantation. The rapid elisas performed well in three IASPs (2011, 2013, 2015) with 98-100% specificity for all three assays, including sensitivities of 64-82% (GADA), 60-64% (IA-2A) and 62-68% (ZnT8A). Since 2009, nPOD has screened 4442 organ donors by rapid elisa; 250 (5·6%) were identified as positive for one AAb and 14 (0.3%) for multiple AAb with 20 of these cases received by nPOD for follow-up studies (14 GADA+, two IA-2A(+) , four multiple AAb-positive). Rapid screening for type 1 diabetes-associated AAb in organ donors is feasible, allowing for identification of non-diabetic, high-risk individuals and procurement of valuable tissues for natural history studies of this disease.

Developing a digital data collection platform to measure the prevalence of sepsis in Wales.

OBJECTIVE: To develop a secure, efficient, and easy-to-use data collection platform to measure the prevalence of sepsis in Wales over 24 hours. MATERIALS AND METHODS: Open Data Kit was used on Android devices with Google App Engine and a digital data collection form. RESULTS: A total of 184 students participated in the study using 59 devices across 16 hospitals, 1198 datasets were submitted, and 97% of participants found the Open Data Kit form easy to use. DISCUSSION: We successfully demonstrated that by combining a reliable Android device, a free open-source data collection framework, a scalable cloud-based server, and a team of 184 medical students, we can deliver a low-cost, highly reliable platform that requires little training or maintenance, providing results immediately on completion of data collection. CONCLUSION: Our platform allowed us to measure, for the first time, the prevalence of sepsis in Wales over 24 hours.

The Anatomical Society core regional anatomy syllabus for undergraduate medicine.

The Anatomical Society's core syllabus for anatomy (2003 and later refined in 2007) set out a series of learning outcomes that an individual medical student should achieve on graduation. The core syllabus, with 182 learning outcomes grouped in body regions, referenced in the General Medical Council's Teaching Tomorrow's Doctors, was open to criticism on the grounds that the learning outcomes were generated by a relatively small group of anatomists, albeit some of whom were clinically qualified. We have therefore used a modified Delphi technique to seek a wider consensus. A Delphi panel was constructed involving 'experts' (n = 39). The revised core syllabus of 156 learning outcomes presented here is applicable to all medical programmes and may be used by curriculum planners, teachers and students alike in addressing the perennial question: 'What do I need to know ?'

Mobilization without immune depletion fails to restore immunological tolerance or preserve beta cell function in recent onset type 1 diabetes.

Granulocyte colony-stimulating factor (G-CSF) has been used to restore immune competence following chemoablative cancer therapy and to promote immunological tolerance in certain settings of autoimmunity. Therefore, we tested the potential of G-CSF to impact type 1 diabetes (T1D) progression in patients with recent-onset disease [n = 14; n = 7 (placebo)] and assessed safety, efficacy and mechanistic effects on the immune system. We hypothesized that pegylated G-CSF (6 mg administered subcutaneously every 2 weeks for 12 weeks) would promote regulatory T cell (Treg) mobilization to a degree capable of restoring immunological tolerance, thus preventing further decline in C-peptide production. Although treatment was well tolerated, G-CSF monotherapy did not affect C-peptide production, glycated haemoglobin (HbA1c) or insulin dose. Mechanistically, G-CSF treatment increased circulating neutrophils during the 12-week course of therapy (P < 0·01) but did not alter Treg frequencies. No effects were observed for CD4(+) : CD8(+) T cell ratio or the ratio of naive : memory (CD45RA(+)/CD45RO(+)) CD4(+) T cells. As expected, manageable bone pain was common in subjects receiving G-CSF, but notably, no severe adverse events such as splenomegaly occurred. This study supports the continued exploration of G-CSF and other mobilizing agents in subjects with T1D, but only when combined with immunodepleting agents where synergistic mechanisms of action have previously demonstrated efficacy towards the preservation of C-peptide.

Factors impeding the discovery of an intervention-based treatment for type 1 diabetes.

Type 1 diabetes (T1D) is one of the most common and severe chronic diseases affecting both children and adults. The aetiology of the disease remains unknown, and thus far no 'true' cure for those affected is available. Indeed, exogenous insulin replacement therapy to manage glucose metabolism to the best degree possible remains the current standard of care. However, despite a recent array of truly impressive improvements designed to enhance disease management (e.g. insulin analogues, continuous glucose monitoring, insulin pumps), it is still difficult for the vast majority of patients to reach recommended target HbA1C levels (< 7.0%). As a result of suboptimal disease management, far too many patients with T1D have an increased risk for disease-associated complications such as nephropathy, neuropathy and retinopathy, as well as hypoglycaemia. New treatment modalities are therefore needed urgently to bring a 'true' cure (disease prevention/disease reversal) to patients with T1D. Here we consider issues that collectively pose a major stumbling block in T1D research with respect to identifying a means to prevent and/or cure the disease. We begin this Perspective by discussing new insights emanating from studies of the pancreas in human T1D; findings which may, at least in part, explain why previous interventions seeking disease prevention/reversal have yielded insufficient benefit. We then turn to suggestions that could optimise the outcome of future clinical trials. Finally, we direct attention to recommendations for the global T1D research community; messages we deem to have the potential to improve our chances of finding the elusive T1D 'cure'.

Realising the European network of biodosimetry: RENEB-status quo.

Creating a sustainable network in biological and retrospective dosimetry that involves a large number of experienced laboratories throughout the European Union (EU) will significantly improve the accident and emergency response capabilities in case of a large-scale radiological emergency. A well-organised cooperative action involving EU laboratories will offer the best chance for fast and trustworthy dose assessments that are urgently needed in an emergency situation. To this end, the EC supports the establishment of a European network in biological dosimetry (RENEB). The RENEB project started in January 2012 involving cooperation of 23 organisations from 16 European countries. The purpose of RENEB is to increase the biodosimetry capacities in case of large-scale radiological emergency scenarios. The progress of the project since its inception is presented, comprising the consolidation process of the network with its operational platform, intercomparison exercises, training activities, proceedings in quality assurance and horizon scanning for new methods and partners. Additionally, the benefit of the network for the radiation research community as a whole is addressed.

The intestinal microbiome in type 1 diabetes.

Few concepts in recent years have garnered more disease research attention than that of the intestinal (i.e. 'gut') microbiome. This emerging interest has included investigations of the microbiome's role in the pathogenesis of a variety of autoimmune disorders, including type 1 diabetes (T1D). Indeed, a growing number of recent studies of patients with T1D or at varying levels of risk for this disease, as well as in animal models of the disorder, lend increasing support to the notion that alterations in the microbiome precede T1D onset. Herein, we review these investigations, examining the mechanisms by which the microbiome may influence T1D development and explore how multi-disciplinary analysis of the microbiome and the host immune response may provide novel biomarkers and therapeutic options for prevention of T1D.